This "Challenge grant" application addresses the Broad challenge area: translational science: Specific challenge topic: 15-NS-103. Demonstration of "proof of concept" for a new therapeutic approach in a neurological disease. Our goal is to utilize a new concept in gene therapy -viral transduction of brain endothelial cells - to provide a reservoir of therapeutic molecules for the treatment of Alzheimer disease (AD). New techniques form Dr Davidson's laboratory have provided ways to engineer the capsid of adenoassociated viruses (AAVs) so that they are targeted specifically to brain capillary endothelial cells. Since the brain capillary network is extraordinarily dense, this provides a mechanism to bathe the CNS in proteins generated by the transduced cells. Dr Hyman has studied amyloid deposition in transgenic models of AD using in vivo multiphoton imaging, which allows determination of the rate of amyloid deposition by longitudinal imaging. The current proposal aims to combine these two state of the art laboratory's efforts. It is already established that inheritance of the apolipoprotein E4 allele (APOE4) increases risk for AD by about 3 fold compared to the common APOE3, whereas inheritance of the rare APOE2 allele is protective, and decreases risk by about half. Age of onset is similarly impacted, with the APOE2 gene associated with a 2 decade delay in onset of dementia compared to APOE4. APOE4 is also associated with much more amyloid deposition in the AD brain than APOE3 or APOE2. We propose to develop, in transgenic mouse models, a way to introduce the APOE2 gene product into the central nervous system by peripheral injection of an AAV targeted specifically to brain endothelia, and test the hypothesis that its intracerebral expression will delay progression of amyloid deposition. Similarly, we have developed a single-chain anti-Abeta antibody which we will test as an alternative means of diminishing amyloid deposition. We postulate that the effective delivery of APOE2 or antibodies to the CNS may lead to a breakthrough in Alzheimer therapy.